This project will evaluate an entirely novel approach to skin cancer treatment applicable to a broad range of topically accessible skin cancers. We propose to co-deliver a potent chemotherapeutic agent and an immune modifier to kill topically accessible cancer cells and simultaneously convert a cutaneous neoplasm into a highly potent patient specific immunogen capable of inducing innate, adaptive, and tumor specific memory immune responses. The strategy is enabled by a unique microneedle array (MNA) delivery device developed and produced in our laboratory. The therapeutic approach is polyfunctional and synergistic. Chemotherapy and adjuvant therapy are combined temporally and spatially. Chemotherapy is used to kill existing tumor cells through immunogenic good death mechanisms that convert dying cells into a rich source of tumor antigen. Simultaneously, a potent adjuvant is delivered to the tumor bed to recruit and activate innate immune responses and antigen presenting cells. This combined therapy is expected to result in both chemotherapeutic and immune-mediated tumor lysis, providing a rich source of full-length autologous tumor antigens in a pro-immunogenic environment that will promote the development of antigenically broad tumor-specific cellular and humoral immunity. This approach has the additional advantage of affording patient and tumor specific immunity by utilizing the patient's tumor directly as a source of immunogen, obviating obstacles related to antigen and tumor heterogeneity. The dissolvable MNAs we have developed can simultaneously deliver chemotherapeutic agent(s) and immune adjuvant(s) to the same cutaneous microenvironment, enabling manipulation of the tumor microenvironment through low dose delivery, with virtually no systemic exposure or toxicity. Further, the biologically active cargos loaded into MNA devices are extremely stable, and eliminate dependency on the cold chain. Together with the ease of fabrication and minimal dosing, these features enable an economically feasible patient specific chemo-immunization. In this project, we will test our hypothesis that in situ topical MNA-directed chemo-immunotherapy will kill tumor cells locally and alter the tumor microenvironment to induce durable systemic tumor specific immunity. In this, the first clinical application of this strategy, our goal is to evaluate MNA-directed chemoimmunotherapy in patients with in-transit melanoma and in CTCL patients through phase l/ll clinical trials. We will evaluate clinical responses and therapy induced immune effects locally and systemically.